The main objective of the research proposal is to reduce the toxicity of bone marrow transplantation (BMT) for sickle cell disease (SCD) in order to extend this potentially curative therapy to more patients. Despite current therapies, SCD is associated with substantial morbidity and mortality. Myeloablative BMT can cure SCD but its application is limited by a 5-10% mortality risk, a 10% failure rate, graft-versus-host disease (GVHD) and the risk of gonadal and endocrine dysfunction. Nonmyeloablative BMT (NST) can result in mixed hematopoietic chimerism, stable co-existence of host and donor marrow, and may be less toxic than myeloablative BMT. Because normal red blood cells (RBCs) survive much longer than sickle RBCs, a low-level of normal donor chimerism may substantially reduce the fraction of sickle cells in the circulation and prevent their pathologic effects. There is limited experience, however, with NST in patients with SCD. We have studied animal models of mixed chimerism to treat SCD, tested novel NST regimens for inducing donor-specific tolerance and reducing GVHD, and piloted a clinical trial of NST in patients with SCD. Six of seven patients treated had initial donor engraftment and toxicities were mild and reversible, however, all patients experienced late graft failure. We now hypothesize that HLA-identical sibling bone marrow will engraft in >80% of patients with SCD who receive pre-transplantation fludarabine and low-dose total body irradiation, with or without cyclophosphamide (Cy), followed by post-transplantation Cy, tacrolimus and mycophenolate mofetil. We will study in-vitro anti-donor reactivity as a predictor of rejection, track other factors associated with engraftment and GVHD, assess immune reconstitution after NST, and evaluate the effect of this treatment on multiple clinical parameters. I was recently recruited to the Children's Hospital of Philadelphia to establish a clinical research program in BMT for non-malignant diseases, emphasizing SCD. My objective is to become an independent clinical scientist by obtaining formal instruction and conducting mentored patient-oriented research on reducing the toxicity of BMT for SCD. I have a strong mentoring committee composed of scientists with expertise in clinical trial development, SCD, BMT, biostatistics, bioethics and transplant biology. As part of my training, I will obtain a Master's Degree in Clinical Research through the Center for Clinical Epidemiology and Biostatistics.